The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA3 adenosine
receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido
and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at
the six-position. Many derivatives show high hA3 adenosine receptor affinities and selectivities both versus hA1 and hA2A receptors.
The observed structure–affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published
ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3-
a]quinoxalin-1-one (13), which shows high hA3 affinity (Ki = 5.5 nM) and selectivity versus hA1, hA2A (both selectivity
ratios > 1800) and hA2B (cAMP assay, IC50 > 10,000 nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving
to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in
delaying the occurrence of anoxic depolarization.

The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA3 adenosine
receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido
and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at
the six-position. Many derivatives show high hA3 adenosine receptor affinities and selectivities both versus hA1 and hA2A receptors.
The observed structure–affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published
ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3-
a]quinoxalin-1-one (13), which shows high hA3 affinity (Ki = 5.5 nM) and selectivity versus hA1, hA2A (both selectivity
ratios > 1800) and hA2B (cAMP assay, IC50 > 10,000 nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving
to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in
delaying the occurrence of anoxic depolarization.